RESUMO
Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR-1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow-up of 24 months for patients receiving axi-cel and 60 months for patients receiving CIT, 12-month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24-0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi-cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi-cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi-cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi-cel in older patients and patients with ECOG PS = 2 with R/R LBCL.
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Produtos Biológicos , Linfoma Difuso de Grandes Células B , Humanos , Idoso , Estudos Retrospectivos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Resposta Patológica Completa , Imunoterapia Adotiva , Antígenos CD19RESUMO
Objective: The present study aimed to establish the test-retest reliability and validity of a tablet-based automated pure-tone screening test and a word-in-noise test as hearing screening tools for older Hong Kong Cantonese-speaking adults.Design and study sample: It was a cross-sectional within-subject study. One hundred and thirty-two older adults participated in this study, and 112 of them completed the automated pure-tone screening test, word-in-noise test, and conventional pure-tone audiometry. Pure-tone threshold of 40 dB HL at each of the tested frequencies including 500, 1000, 2000 and 4000 Hz, obtained with conventional pure-tone audiometry was set as the pass/refer criterion, for the calculation of sensitivity and specificity of the tablet-based screening tools.Results: The tablet-based automated pure-tone screening test yielded a sensitivity of 0.93 and specificity of 0.82, while the word-in-noise test yielded a sensitivity of 0.81 and specificity of 0.70 with the cut-off chosen as a speech reception threshold of -3.5 dB signal-to-noise ratio. Both tests require around 3 minutes to be completed on both ears.Conclusions: The tablet-based pure-tone test and word-in-noise test are reliable and valid to be used as screening tools for hearing loss in the Hong Kong Cantonese-speaking elderly.
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Audiometria de Tons Puros/instrumentação , Computadores de Mão , Perda Auditiva/diagnóstico , Programas de Rastreamento/instrumentação , Teste do Limiar de Recepção da Fala/instrumentação , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Hong Kong , Humanos , Masculino , Programas de Rastreamento/métodos , Ruído , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Razão Sinal-RuídoRESUMO
We conducted a national survey among medical students in China to estimate the prevalence of depressive symptoms and explore associated risk factors based on an established questionnaire composed of demographic information, life events in the past four weeks before survey, and the validated Chinese version of the 21-item Beck's Depression Inventory (BDI). The mean age of enrolled 9010 students was 20.7 (standard deviation: 1.6) years. BDI scores indicated that 19.9% had depressive symptoms based on the cut-off score of 14. Socioeconomic factors and student characteristics such as male sex, low monthly income per capita, father's poor education background, and higher year of study were associated with higher prevalence of depressive symptoms among medical students. Students who studied in comprehensive universities were more likely to have depressive symptoms compared with those from medical universities. Habitual smoking and alcohol drinking, sleep deprivation, and hospitalization or medication for one week or more in the last four weeks also predisposed students to higher risk of depressive symptoms. Our results indicate that depressive symptoms are becoming a highly prevalent health problem among Chinese medical students. Primary and secondary prevention should be prioritized to tackle this issue based on potential risk factors.
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Depressão/epidemiologia , Estudantes de Medicina/estatística & dados numéricos , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , China/epidemiologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Renda , Masculino , Pobreza/estatística & dados numéricos , Prevalência , Escalas de Graduação Psiquiátrica , Fatores de Risco , Fatores Sexuais , Privação do Sono/epidemiologia , Fumar/epidemiologia , Fatores Socioeconômicos , Inquéritos e Questionários , Universidades , Adulto JovemRESUMO
PURPOSE: We explored the diagnostic use of circulating tumor cells in patients with neoadjuvant bladder cancer using enumeration and next generation sequencing. MATERIALS AND METHODS: A total of 20 patients with bladder cancer who were eligible for cisplatin based neoadjuvant chemotherapy were enrolled in an institutional review board approved study. Subjects underwent blood draws at baseline and after 1 cycle of chemotherapy. A total of 11 patients with metastatic bladder cancer and 13 healthy donors were analyzed for comparison. Samples were enriched for circulating tumor cells using the novel IsoFlux™ System microfluidic collection device. Circulating tumor cell counts were analyzed for repeatability and compared with Food and Drug Administration cleared circulating tumor cells. Circulating tumor cells were also analyzed for mutational status using next generation sequencing. RESULTS: Median circulating tumor cell counts were 13 at baseline and 5 at followup in the neoadjuvant group, 29 in the metastatic group and 2 in the healthy group. The concordance of circulating tumor cell levels, defined as low-fewer than 10, medium-11 to 30 and high-greater than 30, across replicate tubes was 100% in 15 preparations. In matched samples the IsoFlux test showed 10 or more circulating tumor cells in 4 of 9 samples (44%) while CellSearch® showed 0 of 9 (0%). At cystectomy 4 months after baseline all 3 patients (100%) with medium/high circulating tumor cell levels at baseline and followup had unfavorable pathological stage disease (T1-T4 or N+). Next generation sequencing analysis showed somatic variant detection in 4 of 8 patients using a targeted cancer panel. All 8 cases (100%) had a medium/high circulating tumor cell level with a circulating tumor cell fraction of greater than 5% purity. CONCLUSIONS: This study demonstrates a potential role for circulating tumor cell assays in the management of bladder cancer. The IsoFlux method of circulating tumor cell detection shows increased sensitivity compared with CellSearch. A next generation sequencing assay is presented with sufficient sensitivity to detect genomic alterations in circulating tumor cells.
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Células Neoplásicas Circulantes , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Projetos Piloto , Estudos Prospectivos , Neoplasias da Bexiga Urinária/terapiaRESUMO
BACKGROUND: Children and adolescents are among the most vulnerable groups affected by natural and man-made disaster. To better understand research and practice concerning mental health and psychosocial support efforts in humanitarian settings, the authors conducted a comprehensive review of all intervention programmes within the past decade that universally targeted children and adolescents who were exposed to a natural and/or man-made disaster. METHODS: We searched PubMed, PsychINFO, Cochrane Library and CINAHL for mental health and psychosocial interventions (MHPSS) involving children and adolescents. A total of 11 studies, 4 from natural disasters and 7 from conflict-affected areas met the inclusion criteria. Effect sizes were calculated using a random effects model for studies in post-natural disaster and war/terrorist-affected settings separately. RESULTS: The weighted mean effect sizes for interventions in both settings were statistically significant: -0.308, 95% CI=-0.54- -0.07, z=-2.58, p=0.010 after a natural disaster, and -0.514, 95% CI=-0.80 to -0.23, z=-3.57, p<0.001 in conflict areas. This indicates that MHPSS interventions in both disaster settings resulted in a reduction in PTSD symptoms compared to the control. CONCLUSIONS: This review suggests that school-based, universal programmes that are conducted by teachers or local paraprofessionals are effective in reducing PTSD symptoms in children and adolescents. The few studies meeting the inclusion criteria of this study demonstrate the need for further expansion of statistical methods and study designs to test for the effects of interventions in challenging humanitarian settings.
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Desastres , Serviços de Saúde Escolar , Sobreviventes/psicologia , Adolescente , Criança , Humanos , Transtornos de Estresse Pós-Traumáticos/prevenção & controleRESUMO
Structural racism is historically rooted, and has been a foundation for United States immigration policy. This injustice has intergenerational effects that cost society greatly - with impacts on social cohesion, individual and collective health, and well-being, and ultimately our ability to function as a civil society. Limited pathways to citizenship and major restrictions to resources that promote integration have adverse consequences for immigrants and, their families. Research shows that children experience toxic stress that negatively impacts their long-term health and development from heightened immigration enforcement, regardless of any personal impact. In embracing the next generation of children, we will not succeed unless we support sound integration policies that promote the health and well-being of immigrant families across this nation. We must recognize how intricately our fates and our health are tied to each other; we all depend on immigrants being well. We must advance new a social contract, one that counters the 'othering' of immigrants" and recognizes that we must invest in the health and well-being of all families.
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Emigrantes e Imigrantes , Humanos , Estados Unidos , Criança , Relação entre Gerações , Racismo Sistêmico , Emigração e Imigração/legislação & jurisprudência , RacismoRESUMO
The efficacy of chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is well-established. This study, using the Premier PINC AI Healthcare Database, assessed hospital costs and healthcare resource utilization (HRU) between CAR T-cell therapy and autologous hematopoietic cell transplant (AHCT) for 733 LBCL patients from 01/01/2017-04/30/2021 (166 CAR T and 567 AHCT from 37 US hospital systems. CAR T-cell therapy had higher index costs but lower non-pharmacy costs, shorter hospital stays, lower ICU utilization than AHCT. The CAR T-cell cohort also presented fewer preparatory costs and HRU. At a 180-day follow-up, AHCT had lower hospitalization rates and costs. Overall, despite higher index costs, CAR T-cell therapy has lower non-pharmacy costs and HRU during the index procedure and requires less preparation time with lower preparation HRUs and costs than AHCT. This has important implications for resource management and informed decision-making for stakeholders.
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Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva/economia , Imunoterapia Adotiva/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Estados Unidos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/economia , Idoso , Receptores de Antígenos Quiméricos , Adulto , Custos de Cuidados de Saúde/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Custos Hospitalares/estatística & dados numéricos , Terapia Combinada/economiaRESUMO
PURPOSE: Although immunotherapies such as blinatumomab and inotuzumab have led to improved outcomes, financial burden and health resource utilization (HRU) have increased for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). This study assessed real-world HRU and costs of care among adult patients with R/R B-ALL by line of therapy (LoT) in the United States. METHODS: We selected patients from the MarketScanâ Database (January 1, 2016 through December 31, 2020) as follows: ≥1 claims of ALL-indicated first-line (1L) therapies, ≥1 diagnosis of ALL before the index date (1L initiation date), 6-month continuous enrollment before the index date, second-line (2L) therapy initiation, ≥18 years old at 2L, no clinical trial enrollment, no diagnosis of other forms of non-Hodgkin's lymphoma, and no claim for daratumumab or nelarabine during the study period. Outcome measures included claim-based time to next treatment (TTNT), all-cause and adverse event (AE)-related HRU, and all-cause and AE-related costs. FINDINGS: The R/R B-ALL cohort (N = 203) was 60% male, median age of 41 years, and median Charlson Comorbidity Index score of 3.0. Mean (SD) follow-up was 17.8 (11.8) months. Of those who received 2L, 55.7% (113/203) required 3L, and 15% (30/203) initiated 4L+. Patients relapsed quickly, with a median TTNT of 170 days, 169 days, and 205 days for 2L, 3L, and 4L+, respectively. Hospitalization rates were high across each LoT (2L, 88%; 3L, 73%; 4L+, 73%), and the mean (SD) inpatient length of stay increased by LoT as follows: 8.6 (6.8) days for 2L, 10.6 (13.3) for 3L, and 11.6 (13.6) for 4L+. Mean (SD) overall costs were substantial within each LoT at $513,279 ($599,209), $340,419 ($333,555), and $390,327 ($332,068) for 2L, 3L, and 4L+, respectively. The mean (SD) overall/per-patient-per-month AE-related costs were $358,676 ($497,998) for 2L, $202,621 ($272,788) for 3L, and $210,539 ($267,814) for 4L+. Among those receiving blinatumomab or inotuzumab within each LoT, the mean (SD) total costs were $566,373 ($621,179), $498,070 ($376,260), and $512,908 ($159,525) for 2L, 3L, and 4L+, respectively. IMPLICATIONS: These findings suggest that adult patients with R/R B-ALL relapse frequently with standard of care and incur a substantial HRU and cost burden with each LoT. Those treated with blinatumomab or inotuzumab incurred higher total costs within each LoT compared with the overall R/R B-ALL cohort. Alternative therapies with longer duration of remission are urgently needed, and HRU should be considered for future studies examining the optimal sequencing of therapy.
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Revisão da Utilização de Seguros , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Masculino , Estados Unidos , Adolescente , Feminino , Estudos Retrospectivos , Aceitação pelo Paciente de Cuidados de Saúde , Hospitalização , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Custos de Cuidados de SaúdeRESUMO
Large B-cell lymphoma (LBCL) is the most common type of non-Hodgkin lymphoma. Chimeric antigen receptor T-cell (CAR T) therapy represents a novel treatment with curative potential for relapsed or refractory (R/R) LBCL, but there are access barriers to this innovative therapy that are not well-studied. Study objectives were: (1) Assess the impact of geographic factors and social determinants of health (SDOH) on access to treatment with CAR T in a sample of patients with R/R LBCL and ≥2 prior lines of therapy (LOT). (2) Compare and contrast patient characteristics, SDOH, and travel time between patients with R/R LBCL who received CAR T and those who did not. An observational, nested case-control study of patients with R/R LBCL, ≥2 prior LOT, not in a clinical trial, identified using 100% Medicare Fee-For-Service and national multi-payer claims databases. Patients were linked to near-neighborhood SDOH using 9-digit ZIP-code address. Driving distance and time between residence and nearest CAR T treatment center (TC) was calculated. Patients were stratified based on treatments received upon third LOT initiation (Index Date) or later: (1) received CAR T and (2) did not receive CAR T. Multivariable logistic regression was used to evaluate factors associated with CAR T. 5011 patients met inclusion criteria, with 628 (12.5%) in the CAR T group. Regression models found the likelihood of receiving CAR T decreased with patient age (odds ratio [OR] = .96, P < .001), and males were 29% more likely to receive CAR T (OR = 1.29, P = .02). Likelihood of CAR T increased with Charlson Comorbidity Index (CCI; OR = 1.07, P < .001) indicating patients with more comorbidities were more likely to receive CAR T. Black patients were less than half as likely to receive CAR T than White patients (OR = .44, P = .01). Asian patients did not significantly differ from White patients (OR = 1.43, P = .24), and there was a trend for Hispanic patients to have a slightly lower likelihood of CAR T (OR = .50, P = .07). Higher household income was associated with receipt of CAR T, with the lowest income group more than 50% less likely to receive CAR T than the highest (OR = .44, P = .002), and the second lowest income group more than 30% less likely (OR = .68, P = .02). Finally, likelihood of CAR T therapy was reduced when the driving time to the nearest TC was 121 to 240 minutes (reference group: ≤30 minutes; OR = .64, P = .04). Travel times between 31 and 121 or greater than 240 minutes were not significantly different from ≤30 minutes. Payer type was collinear with age and could not be included in the regression analysis, but patients with commercial insurance were 1.5 to 3 times more likely to receive CAR T than other payers on an unadjusted basis. We identified significant disparities in access to CAR T related to demographics and SDOH. Patients who were older, female, low income, or Black were less likely to receive CAR T. The positive association of CCI with CAR T requires further research. Given the promising outcomes of CAR T, there is urgent need to address identified disparities and increase efforts to overcome access barriers.
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Acessibilidade aos Serviços de Saúde , Linfoma Difuso de Grandes Células B , Determinantes Sociais da Saúde , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Linfoma Difuso de Grandes Células B/terapia , Estudos de Casos e Controles , Viagem/estatística & dados numéricos , Imunoterapia Adotiva/estatística & dados numéricos , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
INTRODUCTION: Chimeric antigen receptor T-cell (CAR T) therapies have transformed diffuse large B-cell lymphoma (DLBCL) treatment. It is important to better understand their use in Medicare Fee-for-Service (FFS) patients, who often differ from commercially insured populations in important ways. METHODS: We analyzed Medicare FFS claims data, focusing on the utilization patterns across three CAR T products-lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel), and axicabtagene autoleucel (axi-cel)-which are indicated for the treatment of DLBCL. Our investigation covered the period from 2021 through 2022. This analysis spanned a 180-day period prior to CAR T procedure and extended to a 90-day post-CAR T. Utilization of healthcare services, healthcare spending, and comorbidities were assessed in the pre- and post-periods. Clinical trial and PPS-exempt center claims were removed from the analysis. Statistical comparisons between inpatient and outpatient cohorts were made using Wilcoxon's rank-sum tests for continuous variables and Chi-square tests or Fisher's exact tests for categorical variables. RESULTS: Among the total 391 CAR T claims assessed, most of the CAR T therapies were administered in the inpatient setting (79%) compared to outpatient (21%). CAR T therapy in the inpatient setting received an average Medicare cost of US$498,723 ($276,138-$1,066,524), while the average Medicare cost for outpatient CAR T claims was $414,393 ($276,980-$849,878). There was a higher 3-month average post-period cost for those hospitals utilizing CAR T in the outpatient setting than the inpatient setting ($15,794 vs. $10,244). Despite the higher post-period cost, when looking at the CAR T procedure and pre- and post-periods as a single episode, beneficiaries receiving outpatient CAR T had less cost for the total episode of care ($587,908 vs. $529,188). Follow-up inpatient claims were also assessed post-CAR T procedure for 30 days. The rate of post-CAR T inpatient re-admission was significantly lower for beneficiaries receiving the index CAR T in the inpatient setting (21%) compared to outpatient CAR T (59%). Days between index CAR T discharge and IP admission were also significantly shorter for OP CAR T compared to IP CAR T (8.0 vs. 14.1 days, p < 0.0001). Additionally, IP CAR T had a longer ALOS on the admission claim (6.9 vs. 6.2 days). CONCLUSION: CAR T therapy for the treatment of LBCL has become more common within the Medicare population, primarily in the inpatient setting. This study helps understand providers' cost and associated patient care around CAR T administration. The data show that the average cost received by hospitals encompasses the expenses related to both the CAR T drug and the medical services delivered to patients.
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Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Medicare , Humanos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/economia , Estados Unidos , Medicare/economia , Imunoterapia Adotiva/economia , Masculino , Feminino , Idoso , Receptores de Antígenos Quiméricos , Custos de Cuidados de Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Produtos Biológicos , Receptores de Antígenos de Linfócitos TRESUMO
Although clinical and experimental observations indicate that the optic nerve head (ONH) is a major site of axon degeneration in glaucoma, the mechanisms by which local retinal ganglion cell (RGC) axons are injured and damage spreads among axons remain poorly defined. Using a laser-induced ocular hypertension (LIOH) mouse model of glaucoma, we found that within 48 h of intraocular pressure elevation, RGC axon segments within the ONH exhibited ectopic accumulation and colocalization of multiple components of the glutamatergic presynaptic machinery including the vesicular glutamate transporter VGLUT2, several synaptic vesicle marker proteins, glutamate, the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex and active zone cytomatrix components, as well as ultrastructurally identified, synaptophysin-containing vesicles. Ectopic vesicle exocytosis and glutamate release were detected in acute preparations of the LIOH ONH. Immunolocalization and analysis using the ionotropic receptor channel-permeant cation agmatine indicated that ONH axon segments and glia expressed glutamate receptors, and these receptors were more active after LIOH compared with controls. Pharmacological antagonism of glutamate receptors and neuronal activity resulted in increased RGC axon sparing in vivo. Furthermore, in vivo RGC-specific genetic disruption of the vesicular glutamate transporter VGLUT2 or the obligatory NMDA receptor subunit NR1 promoted axon survival in experimental glaucoma. As the inhibition of ectopic glutamate vesicular release or glutamate receptivity can independently modify the severity of RGC axon loss, synaptic release mechanisms may provide useful therapeutic entry points into glaucomatous axon degeneration.
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Axônios/metabolismo , Exocitose/fisiologia , Glaucoma/metabolismo , Ácido Glutâmico/metabolismo , Disco Óptico/metabolismo , Vesículas Secretórias/metabolismo , Animais , Axônios/ultraestrutura , Modelos Animais de Doenças , Pressão Intraocular , Camundongos , Disco Óptico/ultraestrutura , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/ultraestrutura , Vesículas Secretórias/ultraestrutura , Sinapses/metabolismo , Sinapses/ultraestrutura , Sinaptofisina/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismoRESUMO
This study is an evaluation of a psychosocial intervention involving child and adolescent survivors of the 2008 Sichuan China earthquake. Sociodemographics, earthquake-related risk exposure, resilience using the Connor-Davidson Resilience Scale, and posttraumatic stress disorder (PTSD) using the UCLA-PTSD Index were collected from 1,988 intervention participants and 2,132 controls. Mean resilience scores and the odds of PTSD did not vary between groups. The independent factors for risk and resilience and the dependent variable, PTSD, in the measurement models between control and intervention groups were equivalent. The structural model of risk and 2 resilience factors on PTSD was examined and found to be unequivalent between groups. In contrast to controls, risk exposure (B = −0.32, p <.001) in the intervention group was negatively associated with PTSD. Rational thinking (B = −0.48, p < .001), a resilience factor, was more negatively associated with PTSD in the intervention group. The second resilience factor explored, self-awareness, was positively associated with PTSD in both groups (B = 0.46 for controls, p < .001, and B = 0.69 for intervention, p < .001). Results highlight the need for more cross-cultural research in resilience theory to develop culturally appropriate interventions and evaluation measures.
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Desastres , Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Transtornos de Estresse Pós-Traumáticos/psicologia , Sobreviventes/psicologia , Adaptação Psicológica , Adolescente , Conscientização , Criança , China , Terremotos , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino , Escalas de Graduação Psiquiátrica , Fatores de Risco , Esportes/psicologia , PensamentoRESUMO
OBJECTIVES: We assessed real-world healthcare resource utilization (HRU) and costs among US patients with relapsed or refractory mantle cell lymphoma (R/R MCL) by line of therapy (LoT). METHODS: We selected patients from MarketScan® (1/1/2016-12/31/2020): ≥1 claims of MCL-indicated first line (1L) therapies, ≥1 diagnoses of MCL pre-index date (1L initiation date), ≥6-month continuous enrollment pre-index date, second line (2L) therapy initiation, ≥18 years old at 2L, and no clinical trial enrollment. Outcomes included time to next treatment (TTNT), all-cause HRU, and costs. RESULTS: The cohort (N = 142) was 77.5% male, aged 62 years (median). Sixty-six percent and 23% advanced to 3L and 4L+, respectively. Mean (median) TTNT was 9.7 (5.9), 9.3 (5.0), and 6.3 (4.2) months for 2L, 3L, and 4L+, respectively. Mean (median) per patient per month (PPPM) costs were $29,999 ($21,313), $29,352 ($20,033), and $30,633 ($23,662) for 2L, 3L, and 4L+, respectively. Among those who received Bruton tyrosine kinase inhibitors, mean (median) PPPM costs were $24,702 ($17,203), $31,801 ($20,363), and $36,710 ($25,899) for 2L, 3L, and 4L+, respectively. CONCLUSIONS: During the period ending in 2020, patients relapsed frequently, incurring high HRU and costs across LoTs. More effective treatments with long-lasting remissions in R/R MCL may reduce healthcare burden.
Mantle cell lymphoma is a rare blood cancer of white blood cells. This type of cancer can be hard to treat, even with new treatments. In about 15% to 20% of people, the cancer will not get better or will come back within 2 years of starting treatment. When this happens, there are few good options for treatments that work. Using medical claims data, we looked at healthcare use and costs among US patients with mantle cell lymphoma that came back after treatment or did not respond to treatment. We found 142 patients who met the study criteria. Of these, 77.5% were men with a median age of 62 years. Sixty-six percent got a third of the treatment and 23% got a fourth treatment or more. The time until the next treatment was about 910 months for patients who got a second and third treatments.. It was about 6 months for people who got a fourth or more treatment. The average monthly cost of treatment was about $30,000 for those receiving a second or fourth or more treatment. It was slightly less for those who got a third treatment. For those who got Bruton's tyrosine kinase inhibitors, the monthly costs went up with each treatment they needed. Overall, we found that during the study period, patients with mantle cell lymphoma worsened quickly, received multiple treatments, and had high costs of care. Better treatments that work longer are needed.
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Linfoma de Célula do Manto , Adulto , Humanos , Masculino , Estados Unidos , Adolescente , Feminino , Estudos Retrospectivos , Linfoma de Célula do Manto/terapia , Revisão da Utilização de Seguros , Custos e Análise de Custo , Recursos em Saúde , Custos de Cuidados de SaúdeRESUMO
Alterations of abiotic factors due to global climate change are predicted to impact disease dynamics, particularly for pathogens with complex life cycles involving free-living infectious stages, such as the cercariae of trematode parasites. Previous investigations of cercarial output, longevity, and infectivity suggest an overall increase in trematode transmission in response to elevated temperature. However, while increased temperature will likely be accompanied by changes in salinity and pH in marine ecosystems, little is known regarding their influence on cercariae. We investigated the response of trematode cercariae of the intertidal horn snail Cerithidea californica to altered temperature, salinity, and pH. The survival and activity of one trematode species, Euhaplorchis californiensis (Heterophydae), appears to be largely unaffected by increased temperature, while that of a second species, Acanthoparyphium spinulosum (Echinostomatidae), decreased at the warmer temperature (25 degrees C). Cercariae of E. californiensis generally fared best at the highest salinity (40 ppt), whereas A. spinulosum showed the opposite effect. Neither species was affected by pH alone although there were interactions with salinity and time. These results may reflect different emergence patterns of the two species and demonstrate that trematode parasitism in intertidal zones may be impacted by alterations of the marine environment resulting from climate change.
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Gastrópodes/parasitologia , Água do Mar/parasitologia , Trematódeos/fisiologia , Animais , Concentração de Íons de Hidrogênio , Salinidade , Análise de Sobrevida , Temperatura , Trematódeos/efeitos dos fármacos , Trematódeos/efeitos da radiaçãoRESUMO
Protozoan parasites of the genus Leishmania have a digenetic lifecycle, alternating between the promastigote and amastigote stages. The extracellular promastigote resides within a sandfly vector, while the obligate intracellular amastigote stage replicates in the phagolysosome of mammalian host macrophages. Adaptation to and survival within these vastly differently environments is accompanied by differential expression of a subset of genes, which is regulated post-transcriptionally via cis-acting elements in 3' untranslated region (3'UTR) or intercistronic sequences. It was reported previously that Leishmania mexicana A600-4 mRNA transcript abundance was eight-fold higher in the amastigotes. In this study, chimeric luciferase:A600-4 3'UTR reporter constructs were integrated at the A600 chromosome locus to identify regulatory regions of the A600-4 3'UTR sequence. Evidence is provided for distinct 3'UTR elements that function to stabilize the A600-4 mRNA transcript in the amastigote stage and to regulate translation efficiency, respectively.
Assuntos
Regiões 3' não Traduzidas/química , Regulação da Expressão Gênica no Desenvolvimento , Leishmania mexicana/crescimento & desenvolvimento , Estágios do Ciclo de Vida , Biossíntese de Proteínas , Regiões 3' não Traduzidas/genética , Animais , Genes Reporter , Leishmania mexicana/genética , Leishmania mexicana/metabolismo , Luciferases/genética , Luciferases/metabolismo , Dados de Sequência Molecular , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Protozoário/genética , RNA de Protozoário/metabolismo , Análise de Sequência de DNARESUMO
PURPOSE: To identify genes with upregulated expression at the optic nerve head (ONH) that coincides with retinal ganglion cell (RGC) axon loss in glaucomatous DBA/2J mice. To further demonstrate that the proteins encoded by these genes bind to RGC axons and influence fundamental axon physiology. METHODS: In situ hybridization and cell-type-specific immunolabeling were performed on ONH sections from DBA/2J mice (3 to 11 months old) and C57Bl/6NCrl mice (10 months old). EphB2-Fc and ephrin-B2-Fc chimeric proteins were applied to adult RGC axons in vitro and in vivo at the ONH to demonstrate protein binding on axons. EphB2-Fc or control Fc protein was applied in a bath or locally to axons preloaded with the calcium indicator Fluo-4-AM, and changes in intra-axonal calcium were determined. RESULTS: EphB2 and ephrin-B2 were specifically upregulated at the ONH of DBA/2J mice starting at 9 months of age, but not in age-matched C57Bl/6NCrl mice or in DBA/2J animals that did not have axon loss. EphA4 was also present at the ONH, but no difference in expression was detected between unaffected and affected animals. EphB2 was expressed by F4/80(+), MOMA2(+), ED1(-) macrophage-like cells, ephrin-B2 was expressed by Iba-1(+) microglia and GFAP(+) astrocytes, whereas EphA4 was expressed by GFAP(+) astrocytes. EphB2-Fc and ephrin-B2-Fc protein bound to RGC axons in culture and to ONH RGC axons in vivo. Adult RGC axons in vitro elevated intra-axonal calcium in response to EphB2-Fc but not to control Fc protein. CONCLUSIONS: The expression of EphB2 and ephrin-B2 is upregulated at the ONH of glaucomatous DBA/2J mice coinciding with RGC axon loss. The direct binding of EphB2 and ephrin-B2 on adult RGC axons at the ONH and the ability of EphB2 to elevate intra-axonal calcium indicate that these proteins may affect RGC axon physiology in the setting of glaucoma and thus affect the development or progression of the disease.
Assuntos
Axônios/patologia , Efrina-B2/genética , Regulação da Expressão Gênica/fisiologia , Glaucoma/genética , Disco Óptico/metabolismo , Receptor EphB2/genética , Células Ganglionares da Retina/patologia , Animais , Cálcio/metabolismo , Efrina-B2/biossíntese , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Glaucoma/metabolismo , Glaucoma/patologia , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Técnicas de Cultura de Órgãos , RNA Mensageiro/metabolismo , Receptor EphB2/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
BACKGROUND: The 2008 Sichuan earthquake in China destroyed towns and village, displaced over a million people and caused thousands of deaths. There is a need to understand how children and adolescents are able to bounce back after this distressing event. This study conducts a psychometric assessment of the Connor-Davidson Resilience Scale (CD-RISC) and the measure's validity among children and adolescent survivors in order to identify the factors associated with resilience in this socio-cultural setting. METHODS: Translated and culturally verified versions of the CD-RISC, UCLA-PTSD Index and Birleson Self-rating Depression Scale were used to collect data from 2132 children and adolescents located in post-disaster areas 1 year after the event. RESULTS: Through exploratory factor analysis, a 2-factor model was found and defined by Chinese scholars as Rational Thinking and Self-Awareness. Internal consistency of total CD-RISC was 0.86, 0.91 for Rational Thinking and 0.74 for Self-Awareness. Convergent validity between items ranged from 0.17-0.69 and 0.12-0.20 to the total score. Items related to post-traumatic stress disorder loaded separately than CD-RISC items, demonstrating discriminant validity. CONCLUSIONS: Our findings demonstrate that resilience may be understood and manifested dissimilarly in different socio-cultural settings. This study confirms the applicability of the CD-RISC scale to Chinese children and adolescent earthquake survivors, and adds to the richness of resilience research cross-culturally.
Assuntos
Desastres , Terremotos , Escalas de Graduação Psiquiátrica , Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Sobreviventes/psicologia , Adolescente , Criança , China , Estudos Transversais , Características Culturais , Análise Fatorial , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes , Sobreviventes/estatística & dados numéricosRESUMO
PURPOSE: To examine the functional significance of EphB/ephrin-B upregulation in mouse experimental glaucoma. METHODS: In a loss-of-function approach, mouse mutants lacking EphB2 (EphB2(-/-)) or EphB3 (EphB3(-/-)) protein, and mutants expressing EphB2 truncated in the C-terminus (EphB2(lacZ/lacZ)) were subjected to laser-induced ocular hypertension (LIOH), an experimental mouse model of glaucoma. The number of optic nerve axons was counted in paraphenylenediamine (PPD)-stained sections and compared between EphB mutants and wild type littermates. In a gain-of-function approach, retina/optic nerve explants obtained from LIOH-treated animals were exposed to EphB2-Fc recombinant proteins or Fc control proteins. Tissue sections through the optic nerve head (ONH) were labeled with neuron-specific anti-tubulin ß-III antibody to determine axonal integrity. RESULTS: Both EphB2 and EphB3 null mutant mice exhibited more severe axonal degeneration than wild type littermates after treatment with LIOH. Mutant mice in which the C-terminal portion of EphB2 is truncated had an intermediate phenotype. Application of EphB2-Fc recombinant protein to LIOH-treated optic nerve explants resulted in greater sparing of tubulin ß-III-containing retinal ganglion cell (RGC) axons. CONCLUSIONS: These results provide genetic evidence in mice that both EphB/ephrin-B forward and reverse signaling feed into an endogenous pathway to moderate the effects of glaucomatous insult on RGC axons. LIOH-induced axon loss is maintained in retina/optic nerve explants after removal from an ocular hypertensive environment. Exogenous application of EphB2 protein enhances RGC axon survival in explants, suggesting that modulation of Eph/ephrin signaling may be of therapeutic interest.
Assuntos
Axônios/fisiologia , Modelos Animais de Doenças , Efrina-B2/fisiologia , Efrina-B3/fisiologia , Glaucoma/prevenção & controle , Células Ganglionares da Retina/fisiologia , Transdução de Sinais/fisiologia , Animais , Sobrevivência Celular/fisiologia , Corantes/metabolismo , Efrina-B2/farmacologia , Efrina-B3/farmacologia , Glaucoma/metabolismo , Glaucoma/fisiopatologia , Pressão Intraocular , Camundongos , Camundongos Knockout , Microscopia Confocal , Degeneração Neural , Hipertensão Ocular/metabolismo , Hipertensão Ocular/fisiopatologia , Hipertensão Ocular/prevenção & controle , Doenças do Nervo Óptico/metabolismo , Doenças do Nervo Óptico/fisiopatologia , Doenças do Nervo Óptico/prevenção & controle , Técnicas de Cultura de Órgãos , Fenilenodiaminas/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Regulação para CimaRESUMO
PURPOSE: To establish a laser-induced model of ocular hypertension (LIOH) in albino CD-1 mice and to characterize the sequence of pathologic events triggered by intraocular pressure (IOP) elevation. METHODS: LIOH was induced unilaterally in CD-1 mice by laser photocoagulation of limbal and episcleral veins 270 degrees to 300 degrees circumferentially, sparing the nasal aspect and the long ciliary arteries. IOP was measured with a rebound tonometer. Hematoxylin and eosin-stained plastic sections were used for morphometric analysis of retinal layers, and retinal whole-mounts were immunostained with anti-Brn-3b to quantify retinal ganglion cell (RGC) gene expression ion and density. Axonal and myelin morphologies were characterized using appropriate antibodies, and axon counts were obtained from paraphenylenediamine-stained optic nerve sections. RESULTS: LIOH resulted in IOP doubling within 4 hours after laser treatment, which returned to normal by 7 days. Axon degenerative changes, reactive plasticity, and aberrant regrowth were detected at the optic nerve head (ONH) as early as 4 days after treatment. By 7 days, axon number was significantly reduced in the myelinated optic nerve, with concurrent signs of myelin degradation. At 14 days, Brn-3b(+) RGC density was reduced, with neuronal loss confined to the RGC layer and no apparent effects on other retinal layers. CONCLUSIONS: Laser photocoagulation of limbal and episcleral veins induces transient ocular hypertension in albino CD-1 mice. The ensuing retinal and optic nerve pathologic events recapitulated key features of glaucoma and placed ONH RGC axon responses as an early manifestation of damage. LIOH in albino mice may be useful as a mouse model to examine mechanisms of RGC and axon glaucomatous injury.
Assuntos
Modelos Animais de Doenças , Pressão Intraocular , Fotocoagulação a Laser/efeitos adversos , Hipertensão Ocular/etiologia , Células Ganglionares da Retina/patologia , Animais , Axônios/patologia , Biomarcadores/metabolismo , Imuno-Histoquímica , Limbo da Córnea/irrigação sanguínea , Camundongos , Microscopia Confocal , Hipertensão Ocular/metabolismo , Hipertensão Ocular/patologia , Disco Óptico/metabolismo , Disco Óptico/patologia , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/metabolismo , Doenças do Nervo Óptico/patologia , Doenças Retinianas/etiologia , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Células Ganglionares da Retina/metabolismo , Esclera/irrigação sanguínea , Tonometria Ocular , Veias/cirurgiaRESUMO
PURPOSE: To use a laser-induced ocular hypertension (LIOH) mouse model to examine the optic nerve head (ONH) expression of EphB/ephrin-B, previously shown to be upregulated in glaucomatous DBA/2J mice. To relate ephrin-B reverse signaling with states of axonal response to disease. METHODS: LIOH was induced unilaterally in CD-1 mice by laser photocoagulation of limbal and episcleral veins. Intraocular pressure (IOP) was measured with a tonometer. EphB/ephrin-B mRNA expression was assessed by in situ hybridization on eyecup cryosections and real-time PCR. Cell specific markers were used to identify the cellular origin of EphB/ephrin-B expression. Activation of ephrin-B signaling was investigated with a phosphospecific antibody on cryosections and retinal whole-mounts. RESULTS: Upregulation of EphB/ephrin-B expression occurred early within a day of IOP elevation. A transient increase of phosphorylation-dependent ephrin-B (pEB) reverse signaling was observed in ONH axons, microglia, and some astrocytes. Morphologically unaffected retinal ganglion cell (RGC) axons differed from axons with reactive aberrant trajectories by exhibiting increased pEB activation, whereas pEB levels in morphologically affected axons were comparable to those of controls. CONCLUSIONS: An Eph-ephrin signaling network is activated at the ONH after LIOH in CD-1 mice, either before or coincident with the initial morphologic signs of RGC axon damage reported previously. Of note, ephrin-B reverse signaling was transiently upregulated in RGC axons at the ONH early in their response to IOP elevation but was downregulated in axons that had been damaged by glaucomatous injury and exhibited aberrant trajectories. Ephrin-B reverse signaling may mark RGC axons for damage or confer a protective advantage against injury.